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P4‐198: Liposomal delivery of a beta sheet blocker peptide for the treatment of Alzheimer's disease
Author(s) -
Kumaraswamy Priyadharshini,
Sethuraman Swaminathan,
Krishnan Uma Maheswari
Publication year - 2012
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2012.05.1902
Subject(s) - peptide , liposome , amyloid beta , chemistry , beta sheet , biophysics , fibrillogenesis , senile plaques , biochemistry , fibril , alzheimer's disease , pathology , medicine , disease , biology
Background: BACE1 is a key protease targeting the amyloid processing pathways in AD. Previously we published on LY2811376, the first small molecule BACE1 inhibitor reported to provide robust CSF Abeta changes in healthy subjects. LY2811376 progressed to clinical trials but was terminated due to non-clinical tox findings. Here we report the preclinical pharmacology of LY2886721, a new BACE1 inhibitor that is in clinical development for early AD. Methods: Enzyme assays were conducted with recombinant enzymes using a FRET platform. Cell based assays were conducted with either a HEK293Swe cell line or primary neuronal cultures prepared from PDAPP mice. D ose response and time course studies were conducted in young PDAPP transgenic mice with brain collected at various times after oral gavage and extracts analyzed by ELISA for relevant PD biomarkers including Abeta, C99 and sAPPbeta. Plasma and CSF PK/PD studies were conducted in beagle dogs using a multi-week paradigm which involved establishing vehicle-treated baseline CSF Abeta values for within dog comparison to subsequent CSF samples taken from LY-treated dogs. Results: LY2886721 inhibited recombinant hBACE1 with an IC50 of 20.3 nM. In cellular assays, LY2886721 inhibited Abeta with an IC50 of 18.7 nM and 10.7 nM, HEK293Swe and PDAPP neuronal culture, respectively. Oral administration of LY2886721 to PDAPP mice produced dose-dependent reductions in brain Abeta, C99 and sAPPbeta. Brain Abeta levels were decreased w20% -65% relative to vehicle-treated groups three hours after a 3-30 mg/kg dose of LY2886721. Brain C99 and sAPPb levels also were reduced in a dose-dependent manner consistent with BACE1 inhibition in vivo. The pharmacodynamic responses to LY2886721 persisted out to 9 hours post dose in brains of PDAPP mice. Pharmacodynamic studies in beagle dog revealed robust and sustained reductions in plasma Abeta following 1 mg/kg LY2886721 dosing. Central effects of BACE1 inhibition in dog were manifested by a 50% reduction in CSF Abeta at 9 hours after a 0.5 mg/kg dose of LY2886721. Conclusions: LY2886721 is a potent inhibitor of BACE1 which demonstrates robust in vitro and in vivo BACE1 inhibition in pre-clinical models. Phase 2 clinical trials in AD patients are planned for 2012.